1. Pharmacotherapy In Cardiopulmonary Resuscitation (CPR) Dr Abdollahi www.ssu.ac.ir 23 June 20161

2. Cardiac arrest is defined as cessation of cardiac mechanical activity. Cardiopulmonary resuscitation (CPR) is an attempt to restore spontaneous circulation through several maneuvers and techniques. 23 June 20162

3. Aims  Hypoxemia correction  Acidosis correction  Increases perfusion pressure  Increases myocardial contractility  Increase HR  Arrhythmia control  Pain management and pulmonary edema treatment 23 June 20163

4. During cardiac arrest, drug therapy is secondary to more fundamental intervention. Chest compressions, defibrillation (if appropriate), and ventilation should take precedence over medications. Establishing IV access and administering drugs, although important, should not interrupt sustained chest compressions and ventilation. DRUG THERAPY 23 June 20164

5. Oxygen Patients in cardiac arrest or low cardiac output states should receive 100% oxygen as soon as possible. Oxygen will increase arterial oxygen tension and hemoglobin saturation if ventilation is supported and improve tissue oxygenation when circulation is supported. 23 June 20165

6. Of the drugs used during CPR, only vasopressors are acknowledged to help restore spontaneous circulation. 23 June 20166

7. Vasopressor agents given during cardiac arrest aim to improve aortic diastolic pressure. Consequently, increases in coronary and cerebral perfusion pressures enhance both myocardial and cerebral blood flow and improve survival. 23 June 20167

8. 8

9. 9

10. Epinephrine has been used in resuscitation since the 1890s and has been the vasopressor of choice in modern CPR. Vasopressor Agents Mechanism of Action 23 June 201610

11. Epinephrine Epinephrine is a combined direct (α and β- receptor agonist. When epinephrine is administered during CPR, peripheral asoconstriction results in higher aortic pressure causing an increase in coronary and cerebral perfusion pressures and myocardial and brain blood Flows. 23 June 201611

12. Epinephrine When added to chest compressions, epinephrine helps to develop the critical coronary perfusion pressure necessary to provide enough myocardial blood flow for restoration of spontaneous circulation. 23 June 201612

13. Flow to other organs either does not improve or diminishes further when epinephrine is given, despite the increase in aortic pressure. 23 June 201613

14. If invasive monitoring is present during CPR, an arterial diastolic pressure of 40 mm Hg or coronary perfusion pressure of 20 mm Hg must be obtained with good chest compression technique and/or epinephrine therapy. 23 June 201614

15. Current recommendations are to give intravenous epinephrine, 1 mg in the adult or 0.01 mg/kg in children, every 3–5 minutes. Higher doses may be indicated in specific circumstances, or if treatment has been delayed and the standard dose seems ineffective. 23 June 201615

16. 23 June 201616

17. 23 June 201617

18. 23 June 201618

19. 23 June 201619

20. The 4H: 1. Hypoxia 2. Hypovolemia 3. Hyper/hypokalemia, hypocalcemia and acidemia 4. Hypothermia 23 June 201620

21. The 4T: 1. Tension pneumothorax 2. Cardiac tamponade 3. Thromboembolic or mechanical obstruction (e.g.pulmonary embolism) 4. Toxic or therapeutic substances in overdose 23 June 201621

22. Vasopressin Nonadrenergic vasopressors Vasopressin The newest addition to the pharmacologic armamentarium in CPR is arginine vasopressin. It is currently recommended as an alternative to either the first or second dose of epinephrine in a dose of 40 units intravenously. If additional vasopressor doses are needed, epinephrine should be used. The half-life in the intact circulation is 10–20 minutes, and longer than epinephrine during CPR. 23 June 201622

23. It has several advantages over adrenaline in CPR :  Due to lack of the beta effect and impact of acidosis on its efficacy  Lower incidence of post resuscitation myocardial dysfunction. 23 June 201623

24. According to the current CPR guidelines, use of vasopressin as an alternative to adrenaline for shock refractory ventricular fibrillation is recommended as a Class IIb. Use of vasopressin in patients with asystole or pulseless electrical activity (PEA) or in infants and children is recommended as Class indeterminate. It is not established whether a second dose of vasopressin is required or not. 23 June 201624

25. Overall, evidence currently suggests that, like other potent vasopressors, vasopressin is equivalent to, but not better than, epinephrine for use during CPR. 23 June 201625

26. Antiarrythmic agents The use of antiarrythmic drugs has been recommended to aid electrical defibrillation, to prevent the reoccurrence of ventricular fibrillation and to terminate serious electrical arrhythmias. Antiarrythmic drugs should increase the likelihood of successful defibrillation by suppressing a variety of potentially malignant arrhythmias. 23 June 201626

27. Amiodarone Amiodarone should be considered as a Class IIb,following adrenaline, to treat shock refractory VF/VT as early as after three shocks are provided. Amiodarone improves survival to hospital admission but not to hospital discharge because of the side effects such as hypotension and bradycardia 23 June 201627

28. Amiodarone does prevent ventricular arrhythmias and animal studies demonstrated that it could reduce the defibrillation threshold. In an experimental model of persistant VF, animals receiving amiodarone alone had significantly lower resuscitation generated aortic (systolic and diastolic), right atrial systolic and coronary perfusion pressures than did either adrenaline alone or the combination of amiodarone and adrenaline. This study suggested that for optimal hemodynamic support during ongoing CPR adrenaline or other vasoconstrictive agents should be given in combination with, or precede, the administration of amiodarone. 23 June 201628

29. Amiodarone has many different hemodynamic effects. It blocks potassium channels leading to prolongation in the duration of the action potential. It also causes block in sodium and calcium channels and alpha and beta adrenergic receptors. As a result of its direct effect on smooth muscle, and its ability to block calcium channels and alpha adrenergic receptors, amiodarone dilates coronary arteries. It also dilates peripheral arteries leading to vasodilatation and reduction in afterload and systemic blood pressure. Hypotension complicates its use particularly in the setting of a rapid infusion. Therefore, amiodarone is effective in treating most ventricular and supraventricular tachyarrythmias. 23 June 201629

30. The recommended dose of amiodarone is 300 mg diluted in 20 ml 5% dextrose as an iv bolus via a peripheral vein when there is no central venous route. It should be given after the third shock without allowing delay in the delivery of the fourth shock. A further dose of 150 mg amiodarone may be required in refractory cases followed by an infusion of 1 mg min-1 for 6 h and then 0.5 mg/min to a maximum of 2 g in 24 h. However, according to European datasheet maximum dose of amiodarone is 1.2 g in 24 h. 23 June 201630

31. Atropine Atropine sulfate enhances sinus node automaticity and atrioventricular conduction by its vagolytic effects. Atropine is indicated when bradycardia coexists with hypotension, ventricular ectopy, or symptoms associated with myocardial ischemia. 23 June 201631

32. Because atropine has few adverse effects, it can be tried in arrest refractory to epinephrine and oxygenation. The recommended dose for bradycardia in adults is 0.5 mg IV every 3–5 minutes to a total dose of 3.0 mg. The pediatric dose for treating bradycardia is 0.02 mg/kg with a minimum dose of 0.1 mg and a maximum total dose of 1.0 mg in a child and 3.0 mg in an adolescent. The dose may be repeated every 3– 5 minutes. Atropine is no longer recommended for use in pulseless arrest in children. 23 June 201632

33. Calcium Salts With normal cardiovascular physiology, calcium increases myocardial contractility and enhances ventricular automaticity. Consequently, calcium salts have been administered during attempted resuscitation of asystole and EMD for many years. 23 June 201633

34. However, multiple clinical studies have found that calcium is no better than placebo in promoting resuscitation and survival from asystole or EMD. Calcium is not indicated for use during cardiac arrest in adults or children. It may be useful for treatment of hyperkalemia, ionized hypocalcemia, hypermagnesemia or calcium channel blocker toxicity. 23 June 201634

35. If calcium is administrated the chloride salt (2–4 mg/kg) is recommended because it produces higher and more consistent levels of ionized calcium than other salts. 23 June 201635

36. Sodium Bicarbonate Although sodium bicarbonate was used commonly during CPR in the past, there is little evidence to support its efficacy. Its use during resuscitation was predicated on the adverse cardiovascular consequences of acidosis, including impaired myocardial function, decreased catecholamine responsiveness, and peripheral vasodilatation. However, most studies have been unable to demonstrate improvement in success of defibrillation or resuscitation with the use of bicarbonate. 23 June 201636

37. Sodium bicarbonate use during CPR should be restricted not only because of its lack of efficacy but because of the documented complications from excessive use, including hyperosmolality, hypernatremia, metabolic alkalosis and hypercapnia from CO2 liberation. 23 June 201637

38. Lidocaine  LA  Ventricular arrhythmia  Increases VF threshold  Dosage (bolus & infusion) 23 June 201638

39. Lidocaine is a second choice after amiodarone and procainamid. It is acceptable for use in pVT after defibrillation, hemodynamically unstable ventricular premature contractions and hemodynamically stable VT. 23 June 201639

40. The recommended dose is 1-1.5 mg/kg iv bolus and is repeated in the dose of 0.5-0.75 mg/kg not exceeding 3 mg/kg/h. Continuous infusion of 1-4 mg/min is started only if spontaneous circulation returns during CPR. 23 June 201640

41. Toxicity  Decrease CO and cardiovascular depression  CNS irritability (agitation – confusion –auditory – convulsion )  Treatment ( holding – airway – diazepam or barbiturate ) 23 June 201641

42. Procainamide It is an other alternative to amiodarone but the necessity for relatively slow rate of infusion (30 mg min-1 to a total of 17 mg/kg) makes it a less favorable option. 23 June 201642

43. Magnesium The antiarrhythmic action of magnesium is mediated by the activation of membrane sodium-potassium adenosine triphosphatase and blocking of slow calcium channels. Magnesium is universally accepted for the therapy of torsades de pointes. 1-2 g (4-8 mmol) of magnesium sulphate diluted in 100 ml of 5% dextrose is recommended to be given over 30-60 min followed by an infusion of 0.5 -1 g/h. Its use is recommended for shock refractory VF when hypomagnesemia is suspected e.g patients on potassium losing diuretics, because magnesium mirrors the action of extracellular potassium in stabilizing myocardial cell membrane. 23 June 201643

44. 23 June 201644

45. Drug therapy during cardiopulmonary resuscitation Indicationsdose OxygenAll cardiac arrests100% EpinephrineAll cardiac arrests 0.5-1 mg IV (10 μg.kg -1 in children) 1 mg in 10 ml through TT Repeat every 5 minutes consider higher doses in refractory cardiac arrest Sodium bicarbonate Not recommended except in selected patients (hyperkalemia) Adequate alveolar ventilation is the most important factor in management of hypoxic lactic acidosis 1 mEq.kg -1 IV initially; 0.5 mEq.kh -1 IV every 10 minutes of continued CPR or as dictated by PH Lidocaine Recurrent ventricular fibrillation or ventricular fibrillation or ventricular tachycardia 1 mg.kg -1 IV or TT 1-4 mg.min- 1 IV (adult) BretyliumWhen lidocaine is not effective 5 mg.kg -1 IV every 5 minutes; not to exceed 30 mg.kg -1 in an adult Isoproterenol Asystole when atropine is not effective 0.30-0.3 μg.kg -1.min -1 IV (2-20 μg.min -1 IV in adults) AdenostineParoxysmal atrial tachycardia 6-12 mg IV (may repeat once in 1-2 min) Dopamine 5-20 μg.kg -1.min -1 IV Calcium chloride Not recommended except in selected patients for treatment of hypocalcemia or hyperkalemia

46. Conclusion Survival following cardiac arrest mostly depends on the interval between collapse to initiation of CPR and collapse to defibrillation. Although no drug has been reliably proven to increase survival to hospital discharge after cardiac arrest, basic cardiac medication drugs used during ACLS were reviewed. For example; vasopressin has been recommended in case of fibrillatory arrest, the use of lidocaine in refractory ventricular fibrillation remains contentious, whereas amiodarone is recommended after defibrillation and adrenaline. Lidocaine and procainamide are alternatives if amiodarone is not available. 23 June 201646

47. Amiodarone may improve short term survival after out- of-hospital ventricular fibrillation cardiac arrest. Magnesium therapy is recommended especially for torsades de pointes and shock resistant ventricular fibrillation associated with hypomagnesemia. Atropine is the drug of choice in PEA associated with bradycardia and asystole. Sodium bicarbonate and calcium indications are restricted. It is still difficult to say whether drugs used during ACLS are really effective unless further prospective randomized human studies are completed. 23 June 201647

48. 23 June 201648

49. 23 June 201649

50. 23 June 201650

51. 23 June 201651